The Caliciviridae is a family of positive-strand RNA viruses and consists of five genera designated: (1) Norovirus (with species Norwalk virus); (2) Sapovirus (with species Sapporo virus); (3) Vesivirus (with species, feline calicivirus and vesicular exanthema of swine virus); (4) Lagovirus (with species rabbit hemorrhagic disease virus and European brown hare syndrome virus) and (5) Nebovirus (with species Newbury-2 virus). The diseases caused by caliciviruses vary, according to the virus and its host species. The Caliciviruses Section (CS) in LID focuses on caliciviruses associated with diarrheal illness in humans, with an emphasis on the noroviruses because of their predominant role in human disease. Noroviruses are genetically-diverse and most human norovirus pathogens belong to either Genogroup I (GI) or Genogroup II (GII), with GII.4 as the predominant genotype. An important area of investigation is the role of genetic diversity in the natural history of norovirus infection. We made progress this year in the characterization of norovirus genome diversity and in mapping new epitopes in the norovirus virion. A GII.17 norovirus was reported in 2014 as emerging in China, and we identified it for the first time in the U.S. and published the full-length genome sequence. We studied noroviruses associated with chronic and acute illness and followed the evolution of the virus during both types of infection with the latest sequencing technologies. Further characterization of our LID outbreak collection has led to new insight into the role of virus genotype in protective immunity. One approach under consideration for the treatment of norovirus disease is therapeutic antibodies, and we made progress in this area in collaboration with Dr. Viviana Parreno at INTA in Argentina. We published the characterization of two panels of nanobodies (unique single chain antibodies produced in llama) and these molecules are under further investigation at the functional and structural level. One advantage of nanobodies is that they are non-immunogenic and can be administered orally, which makes them attractive as a therapy for clearing norovirus in the intestinal tract. We are also pursuing the GMP-development of a chimpanzee-derived immunoglobulin for clinical testing against the norovirus GII.4 genotype. Following the discontinuation of NIH-supported norovirus research in chimpanzees, we explored the mini-pig as an animal model. We fed well-characterized human norovirus strains to three healthy, young mini-pigs. The pigs remained healthy and did not shed norovirus or show serologic evidence of infection. Human challenge studies are under consideration for future work in the absence of an animal model that fully recapitulates norovirus diarrheal disease.